Diabetic kidney disease is the most important cause of end stage kidney disease in many countries. Recent clinical studies revealed a marked protective effect by SGLT2 inhibitor against cardiovascular disease and kidney disease in diabetic patients. Mechanisms of reno-protection by SGLT2 inhibitor are multifactorial and include amelioration of glomerular hyperfiltration, reduction of oxidative stress, and improvement of kidney oxygenation. Oxidative stress and hypoxia are critical mediators of diabetic kidney disease, and cells are endowed with protective mechanisms of transcription factor, i.e. Nrf2 and HIF. Clinical trials showed that a novel compound to activate Nrf2 can reverse the course of diabetic kidney disease and improve kidney function, although there is a concern about an adverse effect of heart failure. Clinical trials of HIF activators are on-going as a new therapeutic approach of treatment against anemia in CKD. However, it is possible that HIF activators may also be reno-protective by inducing adaptive responses against chronic hypoxia of the kidney in patients with diabetic kidney disease.